Fast track — ArticlesCannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial
Introduction
Of the many symptoms encountered in multiple sclerosis, muscle spasticity (muscle stiffness as a result of increased pyramidal tone) and spasms occur in up to 90% of patients at some point. This symptom often leads to considerable distress from pain, reduced mobility, and interference with activities of daily living. Other disabling features of the disease include ataxia and tremor in up to 80% of patients, and sensory symptoms, including pain, in up to 50%.1 Lower urinary tract dysfunction is present in more than 90% of people with long-standing multiple sclerosis,2 with the most frequent symptoms being urinary frequency and urgency.3 Although many symptoms resolve in the remitting phase of multiple sclerosis, spasticity, weakness, ataxia, and bladder symptoms are often characteristic of progressive disease and tend to worsen over time.
Symptomatic therapy often provides inadequate relief and can be limited by toxicity. As a consequence, people with multiple sclerosis have experimented with many alternative therapies, including cannabis, to ease their physical problems.4, 5 There is much anecdotal suggestion that cannabis and its major components, the cannabinoids, have beneficial effects on disease-related pain, bladder symptoms, tremor, and particularly spasticity,6 but little scientific evidence exists for their efficacy. There is widespread unlicensed and often illegal use of cannabinoids in multiple sclerosis, involving various formulations and routes of administration, and estimates suggest7 that between 1% and 4% of patients in the UK use cannabis for symptom relief.
The plant Cannabis sativa is complex and has more than 60 oxygen-containing aromatic hydrocarbon compounds, known as cannabinoids. Most of their effects seem to be mediated through cannabinoid receptors, two types of which have been isolated and cloned: CB18 and CB2.9 CB1 receptors are distributed widely in the nervous system, and seem to have a general role in the inhibition of neurotransmitter release, whereas CB2 receptors are mainly found on cells of the immune system. The identification of a range of endogenous cannabinoids, the most important of which are thought to be 2-arachidonoylglycerol and arachidonoylethanolamide (anandamide),10 has also provoked considerable interest, and there is some evidence11, 12 that cannabinoids have a neuroprotective action.
Four small, randomised, double-blind, placebocontrolled studies13, 14, 15, 16 have been undertaken to assess the effect of cannabinoids on spasticity related to multiple sclerosis, the largest of which16 was a crossover study of 16 patients. The results suggest that cannabinoids produce subjective symptomatic improvement, but provide no objective evidence for efficacy. Our aim was to ascertain whether either Δ9-tetrahydrocannabinol (Δ9-THC) or an ethanol extract of whole cannabis is effective for the treatment of spasticity and a range of other disease-related symptoms in patients with multiple sclerosis.
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Patients
Between December, 2000, and October, 2002, we enrolled patients aged 18–64 years with clinically definite or laboratory-supported multiple sclerosis who, in the opinion of the treating doctor, had had stable disease for the previous 6 months, with problematic spasticity (Ashworth score of ⩾2 in two or more lower limb muscle groups). Since cannabinoids can potentially affect cardiac function (reducing heart rate and blood pressure), the exclusion criterion of ischaemic heart disease and the
Results
Figure 1 shows the trial profile. Of the 630 patients included in the intention-to-treat analysis, follow-up data on the primary outcome was obtained for 611 (97%). Completion and return of data for the secondary outcome measures was also generally high, with data available for analysis from 84–91% of patients, including for the four questions posed at the end of study.
Table 2 shows the baseline characteristics of the participants. Patients' demographics in the intention-to-treat sample were
Discussion
Treatment with cannabinoids did not improve spasticity associated with multiple sclerosis as measured with the Ashworth scale, but did result in some benefit in secondary outcome measures, assessing mobility and patients' perceptions of the effect of spasticity. These findings are consistent with those of smaller studies,13, 14, 15, 16 which showed some subjective, but no observer-verified, improvement in disease-related spasticity with use of cannabinoids. Our results should be considered in
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